PROJECT SUMMARY/ABSTRACT Cervical cancer is the second leading cause of death in women worldwide. Human papillomavirus (HPV) is the primary causal agent for cervical cancer. Molecular biologic studies have demonstrated that the high-risk HPV types integrate into the genome of the host cell and are able to disrupt numerous signal transduction pathways that lead to uncontrolled cellular proliferation. While we know quite a bit about the biology of the persistent infections, little is understood about: 1) the factors that cause some HPV-exposed women to become HPV-infected and develop precancerous or cancerous lesions, nor 2) the factors that cause other HPV-exposed women to clear the infection rapidly with no sequelae. One area related to prediction of HPV integration and cervical cancer progression that has not been well- studied is the potential susceptibility due to genetic variation in key genetic pathways. The primary studies in this area have focused on genetic variation related to HPV infection, but few have focused on the pathways that could be related to integration. Therefore, the goal of this application is to examine the effects of polymorphisms in a pertinent DNA repair pathway on HPV viral integration in women with normal cervical cytology and those with low-grade or high-grade squamous intraepithelial lesions. Our hypothesis is that women with risk alleles for genes in the non-homologous end-joining DNA repair pathway have greater potential for HPV to integrate into the host cell genome inducing greater chromosome instability and that these "susceptible" women are more likely to present with high-grade lesions or cervical cancer. This goal will be accomplished through three specific aims: 1.) Determine differences in allele frequency for polymorphisms in the non-homologous end-joining (NHEJ) DNA repair pathway among women with low-grade and high-grade intraepithelial lesions compared to those with normal cervical cytology;2) Determine difference in the amount of viral integration present among women with low-grade and high- grade intraepithelial lesions compared to those with normal cervical cytology;and 3) Determine the association between the NHEJ genotypes and viral integration by clinical outcome of cervical dysplasia (e.g., normal, LSIL, HSIL). PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE Cervical cancer is the second leading cause of death in women worldwide, and cervical precancerous lesions contribute billions of dollars per year to health care costs related to their screening and treatment. The main gap in knowledge is related to the factors that cause some HPV-exposed women to become HPV-infected and develop precancerous or cancerous lesions while others clear the infection rapidly with no sequelae. Given this information better public health screening programs could be tailored to a woman's individual risk profile.